Stress is defined by a constellation of responses that occur when the body's ability to cope with a series of demands is exceeded (1). Stress exposure can vary in duration, and it is clear that stress “load”, defined by both the length of exposure as well as the number of stressors present, plays a role in determining the consequences of stress (2). Short-term stress is thought to recruit adaptive responses that promote coping and resilience. However, the mechanisms for driving adaptive change may be difficult to maintain in the face of repeated challenge, and maladaptations can occur when stress is prolonged (3). For example, high stress load is a risk factor for the development of numerous types of affective mental illness, particularly those involving fear and anxiety (4-6). Despite an abundant literature on the effects of stress in the brain, most studies have focused on the effects of acute stress. Thus, the mechanisms that lead to maladaptations following chronic stress exposure are unclear.
While there are many brain regions that are altered by stress and mediate stress-related changes in behavior, the hippocampus is the region in which the effects of stress are best characterized. The hippocampus plays a role in many types of memory (7), and is also linked to affective regulation (8, 9). Acute stress can both enhance and impair hippocampal function. For example, acute stress can increase (10) or decrease (11) hippocampal dendritic spine density. Acute stress can also enhance (12) or impair (13) hippocampus-dependent cognition, perhaps depending on the level of arousal attained during the stress (14). In contrast, chronic stress generally produces dendritic retraction in hippocampus (15-18), and impairs performance on hippocampus-dependent memory tasks (19-21). These changes are thought to be mediated, in part, by stress hormone-induced downregulation of growth factors, such as brain-derived neurotrophic factor, in neurons (22).